1. Field of the Invention
This invention is directed to novel methods for embolizing blood vessels which are particularly suited for treating aneurysms, AVM and high flow fistulas. In one embodiment, the compositions employed in the methods of this invention comprise a biocompatible polymer, a biocompatible solvent and a biocompatible contrast agent wherein the viscosity of this composition is at least about 150 cSt at 40xc2x0 C. and, preferably, at least 200 cSt at 40xc2x0 C.
2. References
The following publications are cited in this application as superscript numbers:
1 Mandai, et al., xe2x80x9cDirect Thrombosis of Aneurysms with Cellulose Acetate Polymerxe2x80x9d, J. Neurosurg., 77:497-500 (1992)
2 Kinugasa, et al., xe2x80x9cDirect Thrombosis of Aneurysms with Cellulose Acetate Polymerxe2x80x9d, J. Neurosurg., 11:501-507 (1992)
3 Casarett and Doull""s Toxicology, Amdur et al., Editors, Pergamon Press, New York, pp. 661-664 (1975)
4 Greff, et al., U.S. Pat. No. 5,667,767 for xe2x80x9cNovel Compositions for Use in Embolizing Blood Vesselsxe2x80x9d, issued Sep. 16, 1997.
5 Greff, et al., U.S. Pat. No. 5,580,568 for xe2x80x9cCellulose Diacetate Compositions for Use in Embolizing Blood Vesselsxe2x80x9d, issued Dec. 3, 1996.
6 Kinugasa, et al., xe2x80x9cEarly Treatment of Subarachnoid Hemorrhage After Preventing Rerupture of an Aneurysmxe2x80x9d, J. Neurosurg., 8:34-41 (1995)
7 Kinugasa, et al., xe2x80x9cProphylactic Thrombosis to Prevent New Bleeding and to Delay Aneurysm Surgeryxe2x80x9d, Neurosurg., 36:661 (1995)
8 Taki, et al., xe2x80x9cSelection and Combination of Various Endovascular Techniques in the Treatment of Giant Aneurysmsxe2x80x9d, J. Neurosurg., 27:37-42 (1992)
9 Evans, et al., U.S. patent application Ser. No. 08/655,822 for xe2x80x9cNovel Compositions for Use in Embolizing Blood Vesselsxe2x80x9d, filed May 31, 1996
10 Dunn, et al., U.S. Pat. No. 4,938,763 for xe2x80x9cBiodegradable In-Situ Forming Implants and Methods of Producing Samexe2x80x9d, issued Jul. 3, 1990
11 Greff, et al., U.S. Pat. No. 5,695,480 for xe2x80x9cNovel Embolizing Compositionsxe2x80x9d, issued Dec. 9, 1997
12 Greff, et al., U.S. Pat. No. 5,830,178 for xe2x80x9cNovel Methods for Embolizing Vascular Sites with an Embolizing Composition Comprising Dimethylsulfoxide, issued Nov. 3, 1998.
All of the above references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated herein by reference in its entirety.
3. State of the Art
Embolization of blood vessels is conducted for a variety of purposes including the treatment of tumors, the treatment of lesions such as aneurysms, uncontrolled bleeding and the like.
Embolization of blood vessels is preferably accomplished via catheter techniques which permit the selective placement of the catheter at the vascular site to be embolized. In this regard, recent advancements in catheter technology as well as in angiography now permit neuroendovascular intervention including the treatment of otherwise inoperable lesions. Specifically, development of microcatheters and guide wires capable of providing access to vessels as small as 1 mm in diameter allows for the endovascular treatment of many lesions.
Embolizing compositions heretofore disclosed in the art include those comprising a biocompatible polymer, a biocompatible solvent and a contrast agent which allowed visualization of the in vivo delivery of the composition via fluoroscopy. 1-8 Such compositions typically contain no more than about 8 weight percent of biocompatible polymer based on the weight of the total composition.
Endovascular treatment regimens preferably include the use of a water insoluble, radiopaque contrast agent in the embolizing compositions in order that the physician can visualize delivery of the composition to the vascular site via conventional techniques such as fluoroscopy. 1-8 Additionally, the use of water insoluble contrast agents is beneficial during post treatment procedures to visualize the embolized mass during, for example, surgery or to monitor the disease condition and/or for retreatment purposes. Visualization is particularly necessary when using catheter delivery techniques in order to ensure both that the composition is being delivered to the intended vascular site and that the requisite amount of composition is delivered. The latter requirement is particularly critical in the treatment of aneurysms where only the aneurysm sac is intended to be filled while leaving the adjoining blood vessel unaffected. Accordingly, in such treatments, the amount of embolic composition delivered is selected to substantially fill but not overflow the aneurysm sac. If less than this amount of embolic composition is delivered to the aneurysm sac, the patient will be left with an active aneurysm which, in some cases, may grow or enlarge. If more than this amount of embolic composition is delivered, the composition will overflow into the adjoining blood vessel which can then embolize this blood vessel as well as the aneurysm. In the case where the affected blood vessel is in or leads to a critical body organ, e.g., the brain, permanent damage due to ischemia will result.
When delivered by catheter, the embolic compositions preferably comprise a biocompatible solvent, a biocompatible polymer and the water insoluble contrast agent. The biocompatible solvent is miscible or soluble in blood or other body fluid and also solubilizes the biocompatible polymer during delivery. The biocompatible polymer is selected to be soluble in the biocompatible solvent but insoluble in blood or other body fluid. The water insoluble contrast agent is suspended in the composition and, as above, permits the physician to fluoroscopically visualize catheter delivery of this composition. Upon contact with the blood or other body fluid, the biocompatible solvent dissipates from the embolic composition whereupon the biocompatible polymer precipitates in the presence of the water insoluble contrast agent and embolizes the blood vessel.
In practice, complications in this procedure have hindered the delivery of the embolic composition into vascular sites. For example, the use of a flow arresting device to limit blood flow during aneurysm treatment by injection of an embolic composition from a catheter has been heretofore suggested.11 However, there are severe limitations placed on the use of such devices in combination with embolic compositions delivered via catheters. For example, in situ solidification of these composition is facilitated by blood transport of the biocompatible solvent away from the growing precipitate. However, a flow arresting device limits the amount of blood flow in the area adjacent the precipitate which, in turn, hinders further precipitate formation. Moreover, blood flow can be arrested for only a short period of time prior to the onset of tissue damage due to ischemia.
In addition, reproducible formation and control of precipitate formed from the embolic composition at the desired vascular site is critical to effectively treat vascular disorders. While techniques heretofore disclosed in the art provide an adequate level of reproducibility12, new methods which enhance the reproducibility of these techniques would be of great value.
In view of the above, the art is in search of improved embolization techniques.
This invention is directed to novel methods for embolizing blood vessels which are particularly suited for treating aneurysms, AVM""s and high flow fistulas. These methods, either singularly or in combination, permit the facile delivery of liquid embolic compositions to vascular sites while overcoming one or more of the problems heretofore associated with vascular embolization by use of these compositions. These methods, either singularly or in combination, further permit the controlled, reproducible formation of an embolic precipitate at the vascular site.
In one aspect, the invention is directed to a method for embolizing a vascular site comprising an opening that is in communication with a vascular vessel by delivering via a catheter to said vascular site a composition comprising (1) a biocompatible polymer; (2) a biocompatible water insoluble contrast agent; and (3) a biocompatible solvent, said method includes:
(a) positioning the distal end of a delivery catheter in said vascular site wherein the delivery catheter is connected to a source of said composition and whereby said composition can be injected into the vascular site through the delivery catheter;
(b) positioning a flow arresting device (e.g., balloon) at the vascular site to be embolized;
(c) activating the flow arresting device (i.e., a device that either controls or reduces blood flow through a vessel) at the vascular site to be embolized such that the activated device substantially arrests blood flow through the vascular site; and
(d) injecting said composition into the vascular site;
(e) deactivating said flow arresting device to permit sufficient blood flow through said vascular site to be embolized such that removal of the biocompatible solvent is facilitated and oxygenated blood is delivered to the tissue distal to said flow arresting device; and
(f) repeating procedures (c)-(e) at least once and as necessary to effect embolization of said vascular site.
Preferably, step (c) comprises inflating a balloon so that the inflated balloon has a diameter that is greater than the inner diameter of the vascular vessel. In one embodiment, the balloon is inflated to a diameter that is about 100% to 130% of the inner diameter of the vascular vessel, and more preferably about 115%.
In another embodiment, after procedure (d), the balloon is deflated until its diameter is about 10% to 90% of the inner diameter of the vascular vessel and allowing at least some of the biocompatible solvent to be removed from the vascular site by entrainment in bodily fluid, e.g., blood. Preferably the diameter is reduced to about 20-25% of the diameter of the vascular vessel.
In another aspect the invention is directed to a method for embolizing a vascular site comprising an opening that is in communication with a vascular vessel by delivering via a catheter into said vascular site a first embolic composition and then a second embolic composition wherein each embolic composition comprises (1) a biocompatible polymer; (2) a biocompatible water insoluble contrast agent; and (3) a biocompatible solvent, said method includes:
(a) positioning the distal end of a delivery catheter in said vascular site wherein the delivery catheter defines a channel that contains first embolic composition and the second embolic composition wherein the first embolic composition is situated adjacent the distal end and the second embolic composition is situated adjacent to the first embolic composition and whereby said first and second embolic compositions can be injected into the vascular site through the delivery catheter and wherein the first embolic composition has a higher concentration or viscosity of biocompatible polymer than the second embolic composition;
(b) injecting the first embolic composition in said vascular site whereby substantially no axial mixing of the first and second embolic compositions occurs in the channel and, thereafter,
(c) injecting the second embolic composition into the vascular site.
As is apparent, the technique is applicable to injecting two or more formulations.
In one embodiment, procedure (b) comprises applying a first force into the channel to inject said first embolic composition into the vascular site and, procedure (c) comprises applying a second force into the channel to inject said second embolic composition into the vascular site wherein the first force is greater than the second force.
In another embodiment, following procedure (b) the first embolic composition forms a nidus (kernel) in the vascular site and following procedure (c) the second embolic forms a precipitate that emanates from the nidus, wherein the precipitate embolizes the vascular site.
In a further aspect, the invention is directed to a method for embolizing a vascular site comprising an opening that is in communication with said site by delivering via a catheter into said site a composition comprising (1) a biocompatible polymer; (2) a biocompatible water insoluble contrast agent; and (3) a biocompatible solvent, said method includes:
(a) positioning the distal end of a delivery catheter into the vascular site wherein the delivery catheter is connected to a source of said composition and whereby said composition can be injected into the vascular site through the delivery catheter;
(b) positioning a flow arresting device at the vascular site to be embolized;
(c) injecting the biocompatible solvent (e.g., DMSO) into the catheter to fill the lumen of said catheter followed by injecting a first amount of said composition into said catheter thereby at least a portion of said biocompatible solvent is ejected from said catheter into the vascular site and washed downstream therefrom;
(d) activating a flow arresting device at the vascular site so that the activated device substantially seals the opening;
(e) injecting the first amount of said composition from said catheter into the vascular site to form a nidus (kernal) of the embolizing composition;
(f) inactivating the flow arresting device;
(g) determining the volume of the vascular site that has been embolized; and
(h) repeating procedures (e), (f), and (g) as needed to embolize the vascular site.
In the above method, repeating procedure (e), (f) and (g) is preferably done at least one.
In one embodiment, prior to procedure (c) said method further comprises:
(i) inflating a balloon to a first size in the vascular vessel so that the opening is substantially sealed; and, before procedure (e)
(j) deflating the balloon.
In another embodiment, procedure (c) comprises:
(1) filling the catheter with biocompatible solvent (e.g., DMSO);
(2) connecting the catheter to the source of the embolic composition; and
(3) injecting the first amount of composition into the vascular vessel.
In other preferred embodiments: (1) the vascular site has an upper surface (fundus) and a base at the opening wherein the base and fundus are spaced apart by a distance D and procedure (a) comprises positioning the distal end of the catheter a distance of about one-third D from the upper surface, (2) procedure (c) takes place while the flow arresting device is deactivated and comprises injecting an amount of the embolic composition into the vascular site and wherein following procedure (c), the method comprises allowing the biocompatible solvent to be flushed out of the vascular site, (3) procedure (e) comprises injecting an amount of the embolic composition and procedure (f) comprises deactivating the device to allow perfusion, and/or (4) procedure (e) comprises injecting for a time period to permit perfusion and procedure (f) comprises deactivating the device to allow perfusion.
In yet another aspect, the invention is directed to a method for embolizing a vascular site comprising an opening that is in communication with a vascular vessel by delivering via a catheter to said vascular site a composition comprising (1) a biocompatible polymer; (2) a biocompatible water insoluble contrast agent; and (3) a biocompatible solvent, said method includes:
(a) positioning the distal end of a delivery catheter in said vascular site wherein the delivery catheter is connected to a source of said composition and whereby said composition can be injected into the vascular site through the delivery catheter;
(b) activating a flow arresting device in the vascular vessel so that the activated device substantially seals the opening and does not occlude the delivery catheter; and
(c) injecting a single mass (bulk) of said composition into the vascular site wherein the single mass is sufficient to substantially fill the vascular site.
In one embodiment, the method further comprises the procedure of measuring the volume of the vascular site before injecting the single mass in said site.
In other embodiments (1) the volume of the single mass that is injected is substantially equal to that of the vascular site, and/or (2) the activated device is kept inflated for a sufficient amount of time until the biocompatible polymer has formed a precipitate at the vascular site.
In yet another aspect the invention is directed to a method for embolizing a vascular site comprising an opening that is in communication with a vascular vessel by delivering via a catheter into said vascular site an embolizing composition including (1) a biocompatible polymer; (2) a biocompatible water insoluble contrast agent; and (3) a biocompatible solvent, said method includes:
(a) positioning the distal end of a delivery catheter into the vascular site wherein the delivery catheter is connected to a source of a first embolizing composition and second embolizing composition and whereby said first and second embolizing compositions can be injected into the vascular site through the delivery catheter and wherein the first embolizing composition has a higher concentration or concentration of biocompatible polymer than the second embolizing composition;
(b) injecting said first embolizing composition into said vascular site to form a nidus (kernel) of the first embolizing composition; and, thereafter,
(c) injecting said second embolizing composition into said vascular site to form a precipitate emanating from the nidus that embolizes the vascular site.
In other embodiments (1) the method prior to procedure (a) further comprises inflating a balloon in the vascular vessel so that the balloon when inflated seals the opening and does not occlude the delivery catheter, and/or (2) the balloon when inflated has a diameter that is greater than the inner diameter of the vascular vessel.
Preferably, the methods employ a device to connect the delivery system (e.g., catheter liner) and the injector (e.g., syringe) to create a blunt interface between delivered liquids.
Preferably, and as noted above, when treating aneurysms, the distal end of the catheter is placed approximately ⅓ from the top of aneurysm.